The African American community has been under-represented in the search for etiologic factors for Alzheimer's disease CAD), despite data showing increased incidence in this ethnic population and evidence that African Americans may have a different constellation of risk factors than those identified in Caucasians. To elucidate genetic risk factors in this population, we propose a clinic-based case-control study of AD in Detroit, Michigan, using 500 cases and 600 controls. In contrast to previous studies limited by small sample sizes, we have a unique opportunity to collect a large African American case control series through our collaboration with the Henry Ford Health System, Health Alliance Plan (HAP), which insures over 500,000 members in southeastern Michigan. We will collect cases from the Neurology Clinic that is part of the Henry Ford Medical Group in Detroit, which sees over 250 new African American AD HAP members per year. The HAP database also provides a large pool of eligible African American controls residing in the same region and seeking care at the same HF clinics. We will focus our investigation on genes related to vascular mechanisms, considering the evidence for shared risk factors for vascular disease and AD; the evidence of common pathogenic pathways for AD and vascular disorders; and the observed overlap of cerebrovascular disease among AD patients upon imaging and at autopsy. This overlap is notably greater among African American patients, possibly leading to earlier clinical presentation and increased severity of disease. Our specific aims are: (1) Collect and evaluate data for 500 cases / 600 controls from HAP, including vascular risk factors, serum protein levels, clinical vascular measurements, and white matter measurements from MRI (cases + subset of 200 controls); (2) Measure SNP and haplotype variation in 10 vascular candidate genes (6-10 SNPs per gene); (3) Compare candidate gene variation between cases and controls, between vascular strata within AD, and between AD cases and controls, stratified by vascular status; and (4) Explore the genetic influence on intermediate vascular factors within and among cases and controls. We will also genotype a set of 50 SNPs located throughout the genome to provide a 'stratification panel' to assess potential confounding due to admixture and to detect genetic outliers within cases or controls. This study, including a detailed analysis of white matter changes, assessment of vascular and other important AD risk factors, use of emerging SNP technologies and statistical methods, and development of new statistical methodology, will provide a more powerful and rigorous genetic approach than previous candidate gene case-control studies. Further, the imaging results will be of great interest clinically, as very few imaging projects of this kind have been carried out in an African American population.